This invention is directed generally to proteinase (also known as xe2x80x9cproteasexe2x80x9d) inhibitors, and, more particularly, to aromatic sulfone hydroxamate compounds (also known as xe2x80x9caromatic sulfone hydroxamic acid compoundsxe2x80x9d) and salts thereof (particularly pharmaceutically acceptable salts) that, inter alia, inhibit matrix metalloproteinase (also known as xe2x80x9cmatrix metalloproteasexe2x80x9d or xe2x80x9cMMPxe2x80x9d) and/or aggrecanase activity. This invention also is directed to pharmaceutical compositions of such compounds and salts, and methods of using such compounds and salts to prevent or treat conditions associated with MMP and/or aggrecanase activity, particularly pathological conditions.
Connective tissue is a required component of all mammals. It provides rigidity, differentiation, attachments, and, in some cases, elasticity. Connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin, and laminin. These biochemicals make up (or are components of) structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea, and vitreous humor.
Under normal conditions, connective tissue turnover and/or repair processes are in equilibrium with connective tissue production. Degradation of connective tissue is carried out by the action of proteinases released from resident tissue cells and/or invading inflammatory or tumor cells.
Matrix metalloproteinases, a family of zinc-dependent proteinases, make up a major class of enzymes involved in degrading connective tissue. Matrix metalloproteinases are divided into classes, with some members having several different names in common use. Examples are: MMP-1 (also known as collagenase 1, fibroblast collagenase, or EC 3.4.24.3); MMP-2 (also known as gelatinase A, 72 kDa gelatinase, basement membrane collagenase, or EC 3.4.24.24), MMP-3 (also known as stromelysin 1 or EC 3.4.24.17), proteoglycanase, MMP-7 (also known as matrilysin), MMP-8 (also known as collagenase II, neutrophil collagenase, or EC 3.4.24.34), MMP-9 (also known as gelatinase B, 92 kDa gelatinase, or EC 3.4.24.35), MMP-10 (also known as stromelysin 2 or EC 3.4.24.22), MMP-1 I (also known as stromelysin 3), MMP-12 (also known as metalloelastase, human macrophage elastase or HME), MMP-13 (also known as collagenase 111), and MMP-14 (also known as MT1-MMP or membrane MMP). See, generally, Woessner, J. F., xe2x80x9cThe Matrix Metalloprotease Familyxe2x80x9d in Matrix Metalloproteinases, pp. 1-14 (Edited by Parks, W. C. and Mecham, R. P., Academic Press, San Diego, Calif. 1998).
Excessive breakdown of connective tissue by MMPs is a feature of many pathological conditions. Inhibition of MMPs therefore provides a control mechanism for tissue decomposition to prevent and/or treat these pathological conditions. Such pathological conditions generally include, for example, tissue destruction, fibrotic diseases, pathological matrix weakening, defective injury repair, cardiovascular diseases, pulmonary diseases, kidney diseases, liver diseases, and diseases of the central nervous system. Specific examples of such conditions include, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, multiple sclerosis, a decubitis ulcer, corneal ulceration, epidermal ulceration, gastric ulceration, tumor metastasis, tumor invasion, tumor angiogenesis, periodontal disease, liver cirrhosis, fibrotic lung disease, emphysema, otosclerosis, atherosclerosis, proteinuria, coronary thrombosis, dilated cardiomyopathy, congestive heart failure, aortic aneurysm, epidermolysis bullosa, bone disease, Alzheimer""s disease, and defective injury repair (e.g., weak repairs, adhesions such as post-surgical adhesions, and scarring).
Matrix metalloproteinases also are involved in the biosynthesis of tumor necrosis factors (TNFs). Tumor necrosis factors are implicated in many pathological conditions. TNF-xcex1, for example, is a cytokine that is presently thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. TNF-xcex1 can cause and/or contribute to the effects of inflammation (e.g., rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, fibrotic diseases, cancer, infectious diseases (e.g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, cardiovascular diseases (e.g., post-ischemic reperfusion injury and congestive heart failure), pulmonary diseases, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, and acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock and hemodynamic shock). Chronic release of active TNF-xcex1 can cause cachexia and anorexia. TNF-xcex1 also can be lethal.
Inhibiting TNF (and related compounds) production and action is an important clinical disease treatment. Matrix metalloproteinase inhibition is one mechanism that can be used. MMP (e.g., collagenase, stromelysin, and gelatinase) inhibitors, for example, have been reported to inhibit TNF-xcex1 release. See, e.g., Gearing et al. Nature 376, 555-557 (1994). See also, McGeehan et al. See also, Nature 376, 558-561 (1994). MMP inhibitors also have been reported to inhibit TNF-xcex1 convertase, a metalloproteinase involved in forming active TNF-xcex1. See, e.g., WIPO Int""l Pub. No. WO 94/24140. See also, WIPO Int""l Pub. No. WO 94/02466. See also, WIPO Int""l Pub. No. WO 97/20824.
Matrix metalloproteinases also are involved in other biochemical processes in mammals. These include control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (xcex2-amyloid precursor protein) to the ainyloid plaque, and inactivation of (xcex1I-protease inhibitor (xcex1I-PI). Inhibiting MMPs therefore may be a mechanism that may be used to control of fertility. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor (e.g., xcex1I-PI) supports the treatment and prevention of pathological conditions such as emphysema, pulmonary diseases, inflammatory diseases, and diseases of aging (e.g., loss of skin or organ stretch and resiliency).
Numerous metalloproteinase inhibitors are known. See, generally, Brown, P. D., xe2x80x9cSynthetic Inhibitors of Matrix Metalloproteinases,xe2x80x9d in Matrix Metalloproteinases, pp. 243-61 (Edited by Parks, W. C. and Mecham, R. P., Academic Press, San Diego, Calif. 1998).
Metalloproteinase inhibitors include, for example, natural biochemicals, such as tissue inhibitor of metalloproteinase (TIMP), xcex12-macroglobulin, and their analogs and derivatives. These are high-molecular-weight protein molecules that form inactive complexes with metalloproteinases.
A number of smaller peptide-like compounds also have been reported to inhibit metalloproteinases. Mercaptoamide peptidyl derivatives, for example, have been reported to inhibit angiotensin coniierting enzyme (also known as ACE) in vitro and in vivo. ACE aids in the production of angiotensin II, a potent pressor substance in mammals. Inhibiting ACE leads to lowering of blood pressure.
A wide variety of thiol compounds have been reported to inhibit MMPs. See, e.g., W095/12389. See also, W096/11209. See also, U.S. Pat. No. 4,595,700. See also, U.S. Pat. No. 6.013,649.
A wide variety of hydroxamate compounds also have been reported to inhibit MMPs. Such compounds reportedly include hydroxamates having a carbon backbone. See, e.g., WIPO Int""l Pub. No. WO 95/29892. See also, WIPO Int""l Pub. No. WO 97/24117. See also, WIPO Int""l Pub. No. WO 97/49679. See also, European Patent No. EP 0 780 386. Such compounds also reportedly include hydroxamates having peptidyl backbones or peptidomimetic backbones. See, e.g., WIPO Int""l Pub. No. WO 90/05719. See also, WIPO Int""l Pub. No. WO 93/20047. See also, WIPO Int""l Pub. No. WO 95/09841. See also, WIPO Int""l Pub. No. WO 96/06074. See also, Schwartz et al., Progr. Med. Chem., 29:271-334(1992). See also, Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). See also, Denis et al., Invest New Drugs, 15(3): 175-185 (1997). Sulfamato hydroxamates have additionally been reported to inhibit MMPs. See, WIPO Int""l Pub. No. WO 00/46221. And various aromatic sulfone hydroxamates have been reported to inhibit MMPs. See, WIPO Int""l Pub. No. WO 99/25687. See also, WIPO Int""l Pub. No. WO 00/50396. See also, WIPO Int""l Pub. No. WO 00/69821.
It is often advantageous for an MMP inhibitor drug to target a certain MMP(s) over another MMP(s). For example, it is typically preferred to inhibit MMP-2, MMP-3, MMP-9, and/or MMP-13 (particularly MMP-13) when treating and/or preventing cancer, inhibiting of metastasis, and inhibiting angiogenesis. It also is typically preferred to inhibit MMP-13 when preventing and/or treating osteoarthritis. See, e.g., Mitchell et al., J Clin. Invest., 97:761-768 (1996). See also, Reboul et al., J Clin. Invest., 97:2011-2019 (1996). Normally, however, it is preferred to use a drug that has little or no inhibitory effect on MMP-1 and MMP-14. This preference stems from the fact that both MMP-1 and MMP-14 are involved in several homeostatic processes, and inhibition of MMP-1 and/or MMP-14 consequently tends to interfere with such processes.
Many known MMP inhibitors exhibit the same or similar inhibitory effects against each of the MMPs. For example, batimastat (a peptidomimetic hydroxamate) has been reported to exhibit IC50 values of from about 1 to about 20 nM against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat (another peptidomimetic hydroxamate) has been reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum similar to batimastat, except that Marimastat reportedly exhibited an IC50 value against MMP-3 of 230 nM. See Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
Meta analysis of data from Phase I/II studies using Marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, and prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although Marimastat exhibited some measure of efficacy via these markers, toxic side effects reportedly were observed. The most common drug-related toxicity of Marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, and then spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction reportedly permits treatment to continue. See Rasmussen et al., Pharmacol Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
Another enzyme implicated in pathological conditions associated with excessive degradation of connective tissue is aggrecanase, particularly aggrecanase-1 (also known as ADAMTS-4). Specifically, articular cartilage contains large amounts of the proteoglycan aggrecan. Proteoglycan aggrecan provides mechanical properties that help articular cartilage in withstanding compressive deformation during joint articulation. The loss of aggrecan fragments and their release into synovial fluid caused by proteolytic cleavages is a central pathophysiological event in osteoarthritis and rheumatoid arthritis. It has been reported that two major cleavage sites exist in the proteolytically sensitive interglobular domains at the N-terminal region of the aggrecan core protein. One of those sites has been reported to be cleaved by several matrix metalloproteases. The other site, however, has been reported to be cleaved by aggrecanase-1. Thus, inhibiting excessive aggrecanase activity provides a method for preventing or treating inflammatory conditions. See generally, Tang, B. L., xe2x80x9cADAMTS: A Novel Family of Extracellular Matrix Proteases,xe2x80x9d Int""l Journal of Biochemistry and Cell Biology, 33, pp. 33-44 (2001). Such diseases reportedly include, for example, osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis. See, e.g., European Patent Application Publ. No. EP 1 081 137 A1.
In addition to inflammatory conditions, there also is evidence that inhibiting aggrecanase may be used for preventing or treating cancer. For example, excessive levels of aggrecanase-1 reportedly have been observed with a ghoma cell line. It also has been postulated that the enzymatic nature of aggrecanase and its similarities with the MMPs would support tumor invasion, metastasis, and angiogenesis. See Tang, Int""l Journal of Biochemistry and Cell Biology, 33, pp. 33-44 (2001).
Various hydroxamate compounds have been reported to inhibit aggrecanase-1. Such compounds include, for example, those described in European Patent Application Publ. No. EP 1 081 137 A1. Such compounds also include, for example, those described in WIPO PCT Int""l Publ. No. WO 00/09000. Such compounds further include, for example, those described in WIPO PCT Int""l Publ. No. WO 00/59874.
In view of the importance of hydroxamate compounds and salts thereof in the prevention or treatment of several MMP- and/or aggrecanase-related pathological conditions and the lack of enzyme specificity exhibited by at least some of the hydroxamates that have been in clinical trials, there continues to be a need for hydroxamates having greater enzyme inhibition specificity (preferably toward MMP-2, MMP-9,MMP-13, and/or aggrecanase, and particularly toward MMP-13 and/or aggrecanase), while exhibiting little or no inhibition of MMP activity essential to normal bodily function (e.g., tissue turnover and repair). The following disclosure describes hydroxamate compounds and salts thereof that tend to exhibit such desirable activities.
This invention is directed to compounds that inhibit MMP (particularly MMP-2, MMP-9, and/or MMP-13) and/or aggrecanase activity, while generally exhibiting relatively little or no inhibition against MMP activity essential to normal bodily function (particularly MMP-1 and MMP-14 activity). This invention also is directed to a method for inhibiting MMP and/or aggrecanase activity, particularly pathological activity. Such a method is particularly suitable to be used with mammals, such as humans, other primates (e.g., monkeys, chimpanzees. etc.), companion animals (e.g., dogs, cats, horses. etc.), farm animals (e.g., goats, sheep, pigs, cattle, etc.), laboratory animals (e.g., mice, rats, etc.), and wild and zoo animals (e.g., wolves, bears, deer, etc.).
Briefly, therefore, the invention is directed in part to a compound or salt thereof The compound has a structure corresponding to Formula X: 
The variables Z, R, E, and Y are described in more detail below.
The present invention also is directed to treatment methods that comprise administering a compound described above (or pharmaceutically-acceptable salt thereof) in an effective amount to a host mammal having a condition associated with pathological metalloprotease and/or aggrecanase activity. A contemplated compound or salt thereof tends to exhibit, for example, inhibitory activity of one or more matrix metalloprotease (MMP) enzymes (e.g., MMP-2, MMP-9 and MMP-13), while exhibiting substantially less inhibition of MMP-1 and/or MMP-14. By xe2x80x9csubstantially lessxe2x80x9d it is meant that a contemplated compound exhibits an IC50 value ratio against one or more of MMP-2, MMP-9, or MMP-13 as compared to its IC50 value against MMP-1 and/or MMp-14 (e.g., IC50 MMP-13:IC50 MMP-1) that is less than about 1:10, preferably less than about 1:100, and most preferably less than about 1:1000 in the in vitro inhibition assay described in the Example section below.
In one embodiment, the process comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to prevent or treat the condition. Such a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease. Specific examples of such conditions include osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, coronary thrombosis, emphysema, proteinuria, and Alzheimer""s disease.
In another embodiment, the prevention or treatment method comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to inhibit matrix metalloprotease-2, matrix metalloprotease-9, and/or matrix metalloprotease-13 activity.
In another embodiment, the prevention or treatment method comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to prevent or treat a condition associated with TNF-xcex1 convertase activity. Examples of such a condition include inflammation, a pulmonary disease, a cardiovascular disease, an autoimmune disease, graft rejection, a fibrotic disease, cancer, an infectious disease, fever, psoriasis, hemorrhage, coagulation, radiation damage, acute-phase responses of shock and sepsis, anorexia, and cachexia.
In another embodiment, the prevention or treatment method comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to prevent or treat a condition associated with aggrecanase activity. Such a condition may be, for example, an inflammatory disease or cancer.
This invention additionally is directed, in part, to pharmaceutical compositions comprising the above-described compounds or pharmaceutically acceptable salts thereof, and the use of those compositions in the above-described prevention or treatment processes.
This invention further is directed, in part, to the use of an above-described compound or pharmaceutically acceptable salt thereof for production of a medicament for use in the treatment of a condition related to MMP activity. As noted above, such a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease.
Further benefits of Applicants"" invention will be apparent to one skilled in the art reading this patent.
This detailed description of preferred embodiments is intended only to acquaint others skilled in the art with Applicants"" invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating the preferred embodiments of this invention, are intended for purposes of illustration only. This invention, therefore, is not limited to the preferred embodiments described in this patent, and may be variously modified.
A. Compounds of this Invention
In accordance with this invention, Applicants have found that certain aromatic sulfone hydroxamates tend to be effective toward inhibiting MMPs, particularly those associated with excessive (or otherwise pathological) breakdown of connective tissue. Specifically, Applicants have found that these hydroxamates tend to be effective for inhibiting MMP-2 MMP-9, and/or MMP-13, which can be particularly destructive to tissue if present or generated in abnormally excessive quantities or concentrations. Applicants also have discovered that many of these hydroxamates tend to be effective toward inhibiting pathological aggrecanase activity. Applicants have further discovered that these hydroxamates tend to be selective toward inhibiting aggrecanase and/or MMPs associated with pathological condition conditions, and tend to avoid excessive inhibition of MMPs (particularly MMP-1 and MMP-14) essential to normal bodily function (e.g., tissue turnover and repair). Applicants have found, for example, that these hydroxamates tend to be particularly active toward inhibiting MMP-2, MMP-9, MMP-13, and/or aggrecanase activity in vitro assays that are generally predictive of in vivo activity, while exhibiting minimal inhibition toward MMP-1 and/or MMP-14 in such assays. Examples of such in vitro assays are discussed in the example section below. Compounds (or salts) that are particularly useful as selective MMP inhibitors exhibit, for example, an in vitro IC50 value against one or more of MMP-2, MMP-9, and MMP-13 that is no greater than about 0.1 times the IC50 value against MMP-1 and/or MMP-14, more preferably no greater than about 0.01 times the IC50 value against MMP-1 and/or MMP-14, and even more preferably 0.001 times the IC50 value against MMP-1 and/or MMP-14.
Without being bound by theory, the advantages of the selectivity of a contemplated compound can be appreciated by considering the roles of the various MMP and aggrecanase enzymes. For example, inhibition of MMP-1 is believed to be undesirable due to the role of MMP-1 as a housekeeping enzyme (i. e., helping to maintain normal connective tissue turnover and repair). Inhibition of MMP-1 can lead to toxicities or side effects such as such as joint or connective tissue deterioration and pain. On the other hand, MMP-13 is believed to be intimately involved in the destruction of joint components in diseases such as osteoarthritis. Thus, potent and selective inhibition of MMP-13 is typically highly desirable because such inhibition can have a positive effect on disease progression in a patient (in addition to having an anti-inflammatory effect).
Another advantage of the compounds and salts of this invention is their tendency to be selective with respect to tumor necrosis factor release and/or tumor necrosis factor receptor release. This provides the physician with another factor to help select the best drug for a particular patient. Without being bound by theory, it is believed that there are multiple factors to this type of selectivity to be considered. The first is that presence of tumor necrosis factor can be desirable for the control of cancer in the organism, so long as TNF is not present in a toxic excess. Thus, uncontrolled inhibition of release of TNF can be counterproductive and actually can be considered an adverse side effect even in cancer patients. In addition, selectivity with respect to inhibition of the release of the tumor necrosis factor receptor can also be desirable. The presence of that receptor can be desirable for maintaining a controlled tumor necrosis level in the mammal by binding excess TNF.
Briefly, therefore, this invention is directed, in part, to a compound or salt thereof (particularly a pharmaceutically acceptable salt thereof). The compound has a structure corresponding to Formula X: 
In some preferred embodiments:
Z is xe2x80x94C(O)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94N(S(O)2R7)xe2x80x94. In some particularly preferred embodiments, Z is xe2x80x94Oxe2x80x94. In other particularly preferred embodiments, Z is xe2x80x94N(R6)xe2x80x94.
R6 is hydrogen, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, carboxy-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, carboxy, C1-C6-alkylcarbonyl, R8R9-aminocarbonyl, aryl-C1-C6-alkyl, arylcarbonyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, halo-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, perfluoro-C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarylcarbonyl, heterocyclylcarbonyl, aryl, heterocyclyl, heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, aminocarbonyl, C1-C6-alkylimino(R10)carbonyl, arylimino(R10)carbonyl, C5-C6-heterocyclylimino(R10)carbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkylcarbonyl, hydroxy-C1-C6-alkylcarbonyl, thiol-C1-C6-alkylcarbonyl, C3-C6-alkenyl, C3-C6-alkynyl, aryloxycarbonyl, R8R9-aminoimino(R10)methyl, R8R9-amino-C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfonyl-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl, or R8R9-amino-C1-C6-alkyl.
In some particularly preferred embodiments, R6 is C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C1-C6-alkylsulfonyl, C3-C6-alkenyl, or C3-C6-alkynyl.
R7 is aryl-C1-C6-alkyl, aryl, heteroaryl, heterocyclyl, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, carboxy-C1-C6-alkyl, or hydroxy-C1-C6-alkyl.
R8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkylcarbonyl, arylcarbonyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryl-C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, carboxy-C1-C6-alkyl, carboxyaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl. Here, the amino-C1-C6-alkyl nitrogen optionally is substituted with up to 2 substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkylcarbonyl. Preferably, no greater than one of R8 and R9 is hydroxy.
Alternatively, R8 and R9, together with the atom to which they are bonded, form a 5- to 8-membered heterocyclic or heteroaryl ring containing up to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
R10 is hydrogen, hydroxy, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryl-C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, carboxy-C1-C6-alkyl, carboxyaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, a sulfoxide of any said thio substituents, a sulfone of any said thio substituents, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl. Here, the amino-C1-C6-alkyl nitrogen optionally is substituted with up to 2 substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkylcarbonyl.
E is a bond, xe2x80x94C(O)xe2x80x94, or xe2x80x94Sxe2x80x94.
Y is hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocyclyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, or aminoalkyl. Here, the aryl, heteroaryl, arylalkyl, or heterocyclyl optionally is substituted with up to 2 substituents independently selected from the group consisting of alkylcarbonyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino. The amino, in turn, optionally is substituted with up to 2 substituents independently selected from the group consisting of alkyl and arylalkyl. In some particularly preferred embodiments, Y comprises a cyclic structure, i.e., Y is optionally substituted aryl, arylalkyl, cycloalkyl, heteroaryl, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, heterocyclyl, or cycloalkyl. In one such embodiment, Y is optionally substituted phenyl. In another such embodiment, Y is optionally substituted phenylmethyl. In still another such embodiment, Y is optionally substituted heteraryl. And in still yet another such embodiment, Y is optionally substituted heteroarylmethyl.
R is hydrogen, cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, arylalkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, arylalkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroarylalkyl, cycloalkyl, heterocylyloxy, heterocylylthio, heterocylylamino, cycloalkyloxy, cycloalkylthio, heteroarylalkoxy, heteroarylalkylthio, arylalkoxy, arylalkylthio, arylalkylamino, heterocylyl, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylcarbonyloxy, arylalkylcarbonyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, aminocarbonyl, or aminoalkyl.
The nitrogen of an R amino may be unsubstituted. Alternatively, the amino nitrogen may be substituted with up two substituents that are independently selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, and alkylcarbonyl. Alternatively, the amino nitrogen optionally may be substituted with two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that: (i) contains from zero to two additional heteroatoms that are independently selected from the group consisting of nitrogen, oxygen, and sulfur; and (ii) optionally is substituted with up to two substituents independently selected from the group consisting of aryl, alkyl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, alkylcarbonyl, cycloalkyl, heterocylylalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocylylalkyl, hydroxyalkoxyalkyl, arylalkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocylylalkoxy, benzofused cycloalkylcarbonyl, heterocyclylalkylcarbonyl, and cycloalkylcarbonyl.
The nitrogen of an R aminocarbonyl is may be unsubstituted. Alternatively, the aminocarbonyl nitrogen may be the reacted amine of an amino acid. Alternatively, the aminocarbonyl nitrogen may be substituted with up to two substituents independently selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroarylalkyl, cycloalkyl, arylalkyl, trifluoromethylalkyl, heterocylylalkyl, benzofused heterocylylalkyl, benzofused cycloalkyl, and N,N-dialkylsubstituted alkylamino-alkyl. Alternatively, the aminocarbonyl nitrogen may be substituted with two substituents such that the two substituents, together with the aminocarbonyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that optionally is substituted with up to two substituents independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocyclylalkyl, hydroxy, hydroxycarbonyl, aryl, arylalkyl, heteroaralkyl, and amino. Here, the amino nitrogen, in turn, optionally is substituted with: (i) two substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl; or (ii) two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring.
The nitrogen of an R aminoalkyl may be unsubstituted. Alternatively, the aminoalkyl nitrogen may be substituted with up to two substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, and alkylcarbonyl. Alternatively, the aminoalkyl nitrogen may be substituted with two substituents such that the two substituents, together with the aminoalkyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring.
In one particularly preferred embodiment, R is halogen (preferably chloro or fluoro, and even more preferably chloro). In another particularly preferred embodiment, R is hydrogen so that the compound corresponds in structure to Formula XA: 
In other embodiments directed to compounds corresponding in structure to Formula X:
Z is xe2x80x94C(O)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94S(O)2xe2x80x94. In one particularly preferred embodiment, Z is xe2x80x94N(R6)xe2x80x94. In another particularly preferred embodiment, Z is xe2x80x94Oxe2x80x94.
R6 is hydrogen, arylalkoxycarbonyl, alkylcarbonyl, alkyl, alkoxyalkyl, cycloalkyl, heteroarylcarbonyl, heteroaryl, cycloalkylalkyl, alkylsulfonyl, haloalkylcarbonyl, alkenyl, alkynyl, and R8R9-aminoalkylcarbonyl.
In some particularly preferred embodiments, R6 is hydrogen, aryl-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkyl (preferably isopropyl), C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroaryl, heteroarylcarbonyl, halo-C1-C6-alkylcarbonyl, or R8R9-amino-C1-C6-alkylcarbonyl.
In other particularly preferred embodiments, R6 is C1-C6-alkyl (preferably ethyl), C1-C6-alkoxy-C1-C6-alkyl (preferably methoxyethyl), C3-C6-cycloalkyl (preferably cyclopropyl), C3-C8-cycloalkyl-C1-C6-alkyl (preferably cyclopropylmethyl), C3-C6-alkenyl (preferably C3-alkenyl), C3-C6-alkynyl (preferably C3-alkynyl), or C1-C6-alkylsulfonyl (preferably methylsulfonyl).
R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylcarbonyl, haloalkyl, and aminoalkyl. Here, the aminoalkyl nitrogen optionally is substituted with up to two substituents independently selected from the group consisting of alkyl.
Alternatively, R8 and R9, together with the atom to which they are bonded, form a 5- to 8-membered heterocyclyl or heteroaryl containing up to 3 (in many instances, no greater than 2) heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Here, any such heterocyclyl or heteroaryl (particularly heterocyclyl) optionally is substituted with one or more substituents independently selected from the group consisting of hydroxy, keto, carboxy, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylalkyl, heterocyclylalkyl, alkoxycarbonyl, and aminoalkyl. The aminoalkyl nitrogen, in turn, optionally is substituted with up to two substituents independently selected from the group consisting of alkyl.
E is a bond, xe2x80x94C(O)xe2x80x94, or xe2x80x94Sxe2x80x94.
Y is cycloalkyl, 2,3-dihydroindolyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. Here, the cycloalkyl, 2,3-dihydroindolyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, keto, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkoxy, alkylcarbonyl, haloalkoxy, alkylthio, alkoxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkoxy, cycloalkylalkoxyalkyl, aryl, arylalkyl, arylalkoxy, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonylalkyl, alkylsulfonyl, amino, aminoalkyl, and aminocarbonyl. These optional substituents, in turn, optionally are substituted with one or more substituents independently selected from the group consisting of halogen, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylcarbonyl. Additionally, the nitrogen of the amino, aminoalkyl, or aminocarbonyl optionally is substituted with up to two substituents independently selected from the group consisting of alkyl and cycloalkylalkyl.
In some preferred embodiments, E is xe2x80x94C(O)xe2x80x94, and Y is heterocyclyl, aryl (particularly phenyl), heteroaryl, or arylmethyl (particularly phenylmethyl). Here, the heterocyclyl, aryl, heteroaryl, or arylmethyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halo-C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, heterocyclyl, heterocyclyl-C1-C6-alkyl, heteroaryl, heteroarylcarbonyl, heterocyclylcarbonyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl. These optional substituents, in turn, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and C1-C6-alkylcarbonyl. Additionally, the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl and C3-C6-cycloalkyl-C1-C6-alkyl.
In other preferred embodiments, E is xe2x80x94C(O)xe2x80x94, and Y is aryl (particularly phenyl), heteroaryl, arylmethyl (particularly phenylmethyl), or heteroarylmethyl. The aryl, heteroaryl, arylmethyl, or heteroarylmethyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl, C2-C6-alkenyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C3-C6-cycloalkyloxy, C3-C6-cycloalkyl-C1-C6-alkoxy, C3-C6-cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, amino, and amino-C1-C6-alkyl. And the nitrogen of the amino or amino-C1-C6-alkyl optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl. In some such preferred embodiments, Y is optionally substituted phenyl. Such compounds include, for example: 
In other such preferred embodiments, Y is optionally substituted heteroaryl. Such compounds include, for example, compounds wherein Y is optionally substituted thienyl: 
In other preferred embodiments, E is a bond, and Y is aryl (particularly phenyl), 2,3-dihydroindolyl, heterocyclyl, or heteroaryl. The aryl, 2,3-dihydroindolyl, heterocyclyl, or heteroaryl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, keto, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, aryl, aminocarbonyl, and C1-C6-alkylsulfonyl. These optional substituents, in turn, also are optionally substituted with one or more substituents independently selected from the group consisting of halogen, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy. Additionally, the nitrogen of the aminocarbonyl optionally is substituted with up to 2 substituents independently selected from the group consisting of C1-C6-alkyl.
In other preferred embodiments, E is a bond, and Y is heteroaryl, aryl (particularly phenyl), or heterocyclyl. The heteroaryl, aryl, or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-alkoxy, and aryl. The optional aryl substituent(s), in turn, optionally is/are substituted with one or more substituents independently selected from the group consisting of halo-C1-C6-alkyl.
In other preferred embodiments, E is xe2x80x94Sxe2x80x94, and Y is cycloalkyl, aryl, arylmethyl, or heteroaryl. The cycloalkyl, aryl (particularly phenyl), arylmethyl (particularly phenylmethyl), or heteroaryl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy.
In other preferred embodiments, E is xe2x80x94Sxe2x80x94, and Y is heteraryl.
In the above embodiments, R preferably is halogen (preferably chloro or fluoro, and even more preferably chloro). Alternatively, R preferably is hydrogen so that the compound corresponds in structure to Formula XA (shown above).
B. Preparation of useful Compounds
Exemplary chemical transformations that can be useful for preparing compounds and salts of this invention are described in detail in, for example, WIPO Int""l Publ. Nos. WO 00/69821 (published Nov. 23, 2000); WO 00/50396 (published Aug. 31, 2000); and 99/25687 (published May 27, 1999). These references are hereby incorporated by reference into this patent. The reader also is referred to the Example section below, which describes the preparation of numerous compounds and salts of this invention.
C. Salts of the Compounds of this Invention
The compounds of this invention can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt""s physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.
Pharmaceutically-acceptable acid addition salts of the compounds of this invention may be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic acid, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.
Pharmaceutically-acceptable base addition salts of the compounds of this invention include, for example, metallic salts and organic salts. Preferred metallic salts include alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts, and other physiological acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts can be made from tertiary amines and quaternary amine salts, such as tromethamine, diethylamine, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl (C1-C6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
Particularly preferred salts of the compounds of this invention include hydrochloric acid (HCl) salts and trifluoroacetate (CF3COOH or TFA) salts.
D. Preventing or Treating Conditions using the Compounds and Salts of this Invention
One embodiment of this invention is directed to a process for preventing or treating a pathological condition associated with MMP activity in a mammal (e.g., a human, companion animal, farm animal, laboratory animal, zoo animal, or wild animal) having or disposed to having such a condition. Such a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, and a central nervous system disease. Specific examples of such conditions include osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, coronary thrombosis, emphysema, proteinuria, and Alzheimer""s disease.
The condition may alternatively (or additionally) be associated with TNF-xcex1 convertase activity. Examples of such a condition include inflammation (e.g., rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, a fibrotic disease, cancer, an infectious disease (e.g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, a cardiovascular disease (e.g., post-ischemic reperfusion injury and congestive heart failure), a pulmonary disease, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock, hemodynamic shock, etc.), cachexia, and anorexia.
The condition may alternatively (or additionally) be associated with aggrecanase activity. Examples of such a condition include inflammation diseases (e.g., osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis) and cancer.
In this patent, the phrase xe2x80x9cpreventing a conditionxe2x80x9d means reducing the risk of (or delaying) the onset of the condition in a mammal that does not have the condition, but is predisposed to having the condition. In contrast, the phrase xe2x80x9ctreating a conditionxe2x80x9d means ameliorating, suppressing, or eradicating an existing condition. The pathological condition may be, for example: (a) the result of pathological MMP and/or aggrecanase activity itself, (b) affected by MMP activity (e.g., diseases associated with TNF-xcex1, and/or (c) affected by aggrecanase activity.
A wide variety of methods may be used alone or in combination to administer the hydroxamates and salt thereof described above. For example, the hydroxamates or salts thereof may be administered orally, parenterally, by inhalation spray, rectally, or topically. Oral administration can be advantageous if, for example, the patient is ambulatory, not hospitalized, and physically able and sufficiently responsible to take drug at the required intervals. This may be true even if the person is being treated with more than one drug for one or more diseases. On the other hand, IV drug administration can be advantageous in, for example, a hospital setting where the dose (and thus the blood levels) can be well controlled. A compound or salt of this invention also can be formulated for IM administration if desired. This route of administration may be desirable for administering prodrugs or regular drug delivery to patients that are either physically weak or have a poor compliance record or require constant drug blood levels.
Typically, a compound (or pharmaceutically acceptable salt thereof) described in this patent is administered in an amount effective to inhibit a target MMP(s). The target MMP is/are typically MMP-2, MMP-9, and/or MMP-13, with MMP-13 often being a particularly preferred target. The preferred total daily dose of the hydroxamate or salt thereof (administered in single or divided doses) is typically from about 0.001 to about 100 mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even more preferably from about 0.01 to about 10 mg/kg (i.e., mg hydroxamate or salt thereof per kg body weight). Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound or salt will be repeated a plurality of times. Multiple doses per day typically may be used to increase the total daily dose, if desired.
Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular hydroxamate or salt thereof employed; whether a drug delivery system is utilized; and whether the hydroxamate or salt thereof is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely, and, therefore, can deviate from the preferred dosage regimen set forth above.
E. Pharmaceutical Compositions Containing the Compounds and Salts of this Invention
This invention also is directed to pharmaceutical compositions comprising a hydroxamate or salt thereof described above, and to methods for making pharmaceutical compositions (or medicaments) comprising a hydroxamate or salt thereof described above.
The preferred composition depends on the method of administration, and typically comprises one or more conventional pharmaceutically acceptable carriers, adjuvants, and/or vehicles. Formulation of drugs is generally discussed in, for example, Hoover, John E., Remington""s Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.: 1975). See also, Liberman, H. A. See also, Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N.Y., 1980).
Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the hydroxamates or salts thereof are ordinarily combined with one or more adjuvants. If administered per os, the hydroxamates or salts thereof can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation, as can be provided in a dispersion of the hydroxamate or salt thereof in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can be prepared with enteric coatings.
Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
xe2x80x9cParenteral administrationxe2x80x9d includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. Acceptable vehicles and solvents include, for example, water, 1,3-butanediol, Ringer""s solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids (e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic and non-ionic detergents), and/or polyethylene glycols.
Formulations for parenteral administration may, for example, be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The hydroxamates or salts thereof can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
Suppositories for rectal administration can be prepared by, for example, mixing the drug with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, such as cocoa butter; synthetic mono-, di-, or triglycerides; fatty acids; and/or polyethylene glycols
xe2x80x9cTopical administrationxe2x80x9d includes the use of transdermal administration, such as transdermal patches or iontophoresis devices.
Other adjuvants and modes of administration known in the pharmaceutical art may also be used.
F. Definitions
The term xe2x80x9calkylxe2x80x9d (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbyl group typically containing from 1 to about 20 carbon atoms, more typically from about 1 to about 8 carbon atoms, and even more typically from about 1 to about 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like.
The term xe2x80x9calkenylxe2x80x9d (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl group containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such groups include ethenyl (vinyl); 2-propenyl; 3-propenyl; 1,4-pentadienyl; 1,4-butadienyl; 1-butenyl; 2-butenyl; 3-butenyl; decenyl; and the like.
The term xe2x80x9calkynylxe2x80x9d (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl group containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such groups include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
The term xe2x80x9ccarbocyclylxe2x80x9d (alone or in combination with another term(s)) means a saturated cyclic, partially saturated cyclic, or aryl hydrocarbyl group containing from 3 to 14 carbon ring atoms (xe2x80x9cring atomsxe2x80x9d are the atoms bound together to form the ring or rings of a cyclic group). A carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as xe2x80x9ctetralinylxe2x80x9d), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as xe2x80x9cphenalenylxe2x80x9d), fluoreneyl, decalinyl, and norpinanyl.
The term xe2x80x9ccycloalkylxe2x80x9d (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl group containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropanyl, cyclobutanyl, cyclopentyl, and cyclohexyl. A cycloalkyl alternatively may be 2 or 3 carbon rings fused together, such as, decalinyl or norpinanyl.
The term xe2x80x9carylxe2x80x9d (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
In some instances, the number of carbon atoms in a hydrocarbyl group (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix xe2x80x9cCx-Cy-xe2x80x9d, wherein x is the minimum and y is the maximum number of carbon atoms in the group. Thus, for example, xe2x80x9cC1-C6-alkylxe2x80x9d refers to an alkyl group containing from 1 to 6 carbon atoms. Illustrating further, C3-C6-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
The term xe2x80x9chydrogenxe2x80x9d (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as xe2x80x94H.
The term xe2x80x9chydroxyxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94OH.
The term xe2x80x9cnitroxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94NO2.
The term xe2x80x9ccyanoxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94CN, which also may be depicted as or xe2x80x94COOH: 
The term xe2x80x9cketoxe2x80x9d (alone or in combination with another term(s)) means an oxo radical, and may be depicted as xe2x95x90O.
The term xe2x80x9ccarboxyxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94OH, which also may be depicted as: 
The term xe2x80x9caminoxe2x80x9d (alone or incombination with another term(s)) means xe2x80x94NH2. The term xe2x80x9cmonosubstituted aminoxe2x80x9d (alone or in combination with another term(s)) means an amino group wherein one of the hydrogen radicals is replaced by a non-hydrogen substituent. The term xe2x80x9cdisubstituted aminoxe2x80x9d (alone or in combination with another term(s)) means an amino group wherein both of the hydrogen atoms are replaced by non-hydrogen substituents, which may be identical or different.
The term xe2x80x9chalogenxe2x80x9d (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as xe2x80x94F), chlorine radical (which may be depicted as xe2x80x94Cl), bromine radical (which may be depicted as xe2x80x94Br), or iodine radical (which may be depicted as xe2x80x94I). Typically, a fluorine radical or chlorine radical is preferred.
If a group is described as being xe2x80x9csubstitutedxe2x80x9d, at least one hydrogen on the group is replaced with a non-hydrogen substituent. Thus, for example, a substituted alkyl group is an alkyl group wherein at least one hydrogen on the alkyl group is replaced with a non-hydrogen substituent. It should be recognized that if there are more than one substitutions on a group, each non-hydrogen substituent may be identical or different.
If a group is described as being xe2x80x9coptionally substitutedxe2x80x9d, the group may be either substituted or not substituted.
The prefix xe2x80x9chalo xe2x80x9d indicates that the group to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl group wherein at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like. Illustrating further, xe2x80x9chaloalkoxyxe2x80x9d means an alkoxy group wherein at least one hydrogen radical is replaced by a halogen radical. Examples of haloalkoxy groups include chlormethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as xe2x80x9cperfluoromethyoxyxe2x80x9d), 1,1,1,-trifluoroethoxy, and the like. It should be recognized that if a group is substituted by more than one halogen radical, those halogen radicals may be identical or different.
The prefix xe2x80x9cperhaloxe2x80x9d indicates that every hydrogen radical on the group to which the prefix is attached is replaced with independently selected halogen radicals, i.e., each hydrogen radical on the group is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term xe2x80x9cperfluoroxe2x80x9d means that every hydrogen radical on the group to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term xe2x80x9cprefluoroalkylxe2x80x9d means an alkyl group wherein each hydrogen radical is replaced with a fluorine radical. Examples of perfluoroalkyl groups include trifluoromethyl (xe2x80x94CF3), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, perfluorodecyl, and the like. To illustrate further, the term xe2x80x9cperfluoroalkoxyxe2x80x9d means an alkoxy group wherein each hydrogen radical is replaced with a fluorine radical. Examples of perfluoroalkoxy groups include trifluoromethoxy (xe2x80x94Oxe2x80x94CF3), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, perfluorodecoxy, and the like.
The term xe2x80x9ccarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94, which also may be depicted as: 
This term also is intended to encompass a hydrated carbonyl group, i.e., xe2x80x94C(OH)2xe2x80x94.
The term xe2x80x9caminocarbonylxe2x80x9d (alone or incombination with another term(s)) means xe2x80x94C(O)xe2x80x94NH2, which also may be depicted as: 
The term xe2x80x9coxyxe2x80x9d (alone or incombination with another term(s)) means an ether group, and may be depicted as xe2x80x94Oxe2x80x94.
The term xe2x80x9calkoxyxe2x80x9d (alone or incombination with another term(s)) means an alkylether group, i.e., xe2x80x94O-alkyl. Examples of such a group include methoxy (xe2x80x94Oxe2x80x94CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
The term xe2x80x9calkylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-alkyl. For example, xe2x80x9cethylcarbonylxe2x80x9d may be depicted as: 
The term xe2x80x9caminoalkylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-alkylxe2x80x94NH2. For example, xe2x80x9caminomethylcarbonylxe2x80x9d may be depicted as: 
The term xe2x80x9calkoxycarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94O-alkyl. For example, xe2x80x9cethoxycarbonylxe2x80x9d may be depicted as: 
The term xe2x80x9ccarbocyclylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-carbocyclyl. For example, xe2x80x9cphenylcarbonylxe2x80x9d may be depicted as: 
Similarly, the term xe2x80x9cheterocyclylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-heterocyclyl.
The term xe2x80x9ccarbocyclylalkylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-alkyl-carbocyclyl. For example, xe2x80x9cphenylethylcarbonylxe2x80x9d may be depicted as: 
Similarly, the term xe2x80x9cheterocyclylalkylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-alkyl-heterocyclyl.
The term xe2x80x9ccarbocyclyloxycarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94O-carbocyclyl. For example, xe2x80x9cphenyloxycarbonylxe2x80x9d may be depicted as: 
The term xe2x80x9ccarbocyclylalkoxycarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94O-alkyl-carbocyclyl. For example, xe2x80x9cphenylethoxycarbonylxe2x80x9d maybe depicted as: 
The term xe2x80x9cthioxe2x80x9d or xe2x80x9cthiaxe2x80x9d (alone or in combination with another term(s)) means a thiaether group, i.e., an ether group wherein the ether oxygen atom is replaced by a sulfur atom. Such a group may be depicted as xe2x80x94Sxe2x80x94. This, for example, xe2x80x9calkyl-thio-alkylxe2x80x9d means alkyl-S-alkyl.
The term xe2x80x9cthiolxe2x80x9d or xe2x80x9csulfhydrylxe2x80x9d (alone or in combination with another term(s)) means a sulfhydryl group, and may be depicted as xe2x80x94SH.
The term xe2x80x9c(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a group may be depicted as xe2x80x94C(S)xe2x80x94, and also may be depicted as: 
The term xe2x80x9calkyl(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)-alkyl. For example, xe2x80x9cethyl(thiocarbonyl)xe2x80x9d may be depicted as: 
The term xe2x80x9calkoxy(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)xe2x80x94O-alkyl. For example, xe2x80x9cethoxy(thiocarbonyl)xe2x80x9d may may be depicted as: 
The term xe2x80x9ccarbocyclyl(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)-carbocyclyl. For example, xe2x80x9cphenyl(thiocarbonyl)xe2x80x9d may be depicted as: 
Similarly, the term xe2x80x9cheterocyclyl(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)-heterocyclyl.
The term xe2x80x9ccarbocyclylalkyl(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)-alkyl-carbocyclyl. For example, xe2x80x9cphenylethyl(thiocarbonyl)xe2x80x9d may be depicted as: 
Similarly, the term xe2x80x9cheterocyclylalkyl(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)-alkyl-heterocyclyl.
The term xe2x80x9ccarbocyclyloxy(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)xe2x80x94O-carbocyclyl. For example, xe2x80x9cphenyloxy(thiocarbonyl)xe2x80x9d may be depicted as: 
The term xe2x80x9ccarbocyclylalkoxy(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)xe2x80x94O-alkyl-carbocyclyl. For example, xe2x80x9cphenylethoxy(thiocarbonyl)xe2x80x9d maybe depicted as: 
The term xe2x80x9csulfonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94S(O)2xe2x80x94, which also may be depicted as: 
Thus, for example, xe2x80x9calkyl-sulfonyl-alkylxe2x80x9d means alkyl-S(O)2-alkyl.
The term xe2x80x9caminosulfonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94S(O)2xe2x80x94NH2, which also may be depicted as: 
The term xe2x80x9csulfoxidoxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94S(O)xe2x80x94, which also may be depicted as: 
Thus,for example, xe2x80x9calkyl-sulfoxido-alkylxe2x80x9d means alkyl-S(O)-alkyl.
The term xe2x80x9cheterocyclylxe2x80x9d (alone or in combination with another term(s)) means a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. A heterocyclyl alternatively may be 2 or 3 rings fused together.
The term xe2x80x9cheteroarylxe2x80x9d (alone or in combination with another term(s)) means an aromatic ring containing from 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring, which typically contains from 5 to 7 ring atoms, and more typically from 5 to 6 ring atoms. A heteroaryl alternatively may be 2 or 3 rings fused together.
Examples of single-ring heterocyclyls and heteroaryls include furanyl, dihydrofurnayl, tetradydrofurnayl, thiophenyl (also known as xe2x80x9cthiofuranylxe2x80x9d), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as xe2x80x9cazoximylxe2x80x9d), 1,2,5-oxadiazolyl (also known as xe2x80x9cfurazanylxe2x80x9d), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including 1,2-pyranyl or 1,4-pyranyl), dihydropyranyl, pyridinyl (also known as xe2x80x9cazinylxe2x80x9d), piperidinyl, diazinyl (including pyridazinyl (also known as xe2x80x9c1,2-diazinylxe2x80x9d), pyrimidinyl (also known as xe2x80x9c1,3-diazinylxe2x80x9d), or pyrazinyl (also known as xe2x80x9c1,4-diazinylxe2x80x9d)), piperazinyl, triazinyl (including s-triazinyl (also known as xe2x80x9c1,3,5-triazinylxe2x80x9d), as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also known as xe2x80x9c1,2,3-triazinylxe2x80x9d)), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as xe2x80x9cpentoxazolylxe2x80x9d), 1,2,6-oxazinyl, or 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.
Examples of heterocyclyl and heteroaryl rings having 2 or 3 rings fused together include, for example, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of fused-ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (also known as xe2x80x9cisobenzazolylxe2x80x9d or xe2x80x9cpseudoisoindolylxe2x80x9d), indoleninyl (also known as xe2x80x9cpseudoindolylxe2x80x9d), isoindazolyl (also known as xe2x80x9cbenzpyrazolylxe2x80x9d), benzazinyl (including quinolinyl (also known as xe2x80x9c1-benzazinylxe2x80x9d) or isoquinolinyl (also known as xe2x80x9c2-benzazinylxe2x80x9d)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as xe2x80x9c1,2-benzodiazinylxe2x80x9d) or quinazolinyl (also known as xe2x80x9c1,3-benzodiazinylxe2x80x9d)), benzopyranyl (including xe2x80x9cchromanylxe2x80x9d or xe2x80x9cisochromanylxe2x80x9d), benzothiopyranyl (also known as xe2x80x9cthiochromanylxe2x80x9d), benzoxazolyl, indoxazinyl (also known as xe2x80x9cbenzisoxazolylxe2x80x9d), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as xe2x80x9ccoumaronylxe2x80x9d), isobenzofuranyl, benzothienyl (also known as xe2x80x9cbenzothiophenylxe2x80x9d, xe2x80x9cthionaphthenylxe2x80x9d, or xe2x80x9cbenzothiofuranylxe2x80x9d), isobenzothienyl (also known as xe2x80x9cisobenzothiophenylxe2x80x9d, xe2x80x9cisothionaphthenylxe2x80x9d, or xe2x80x9cisobenzothiofuranylxe2x80x9d), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl ), benzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl), tetrahydroisoquinolinyl , carbazolyl, xanthenyl, and acridinyl.
As may be seen in the preceding paragraphs, the term xe2x80x9cheteroarylxe2x80x9d includes 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3-tiiazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as 1,2-, 1,4-, 2,3- and 2, 1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl.
A carbocyclyl, heterocyclyl, or heteroaryl optionally can be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as xe2x80x9calkanoylxe2x80x9d), aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, and cycloalkylalkoxycarbonyl. More typically, a carbocyclyl or heterocyclyl may optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94C(O)xe2x80x94OH, keto, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylcarbonyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkoxy-C1-C6-alkyl, aryl-C1-C6-alkoxycarbonyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, cycloalkyl-C1-C6-alkoxy, cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, and cycloalkyl-C1-C6-alkoxycarbonyl. The alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, or arylalkoxycarbonyl substituent(s) may further be substituted with, for example, one or more halogen. The aryls or cycloalkyls are typically single-ring groups containing from 3 to 6 ring atoms, and more typically from 5 to 6 ring atoms.
An aryl or heteroaryl optionally can be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SH, xe2x80x94C(O)xe2x80x94OH, amino, aminocarbonyl, aminoalkyl, alkyl, alkylthio, carboxyalkylthio, alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxyalkylthio, alkoxycarbonylalkylthio, carboxyalkoxy, alkoxycarbonylalkoxy, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, carbocyclylthio, carbocyclylalkylthio, carbocyclylamino, carbocyclylalkylamino, carbocyclylcarbonylamino, carbocyclylcarbonyl, carbocyclylalkyl, carbonyl, carbocyclylcarbonyloxy, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, carbocyclyloxyalkoxycarbocyclyl, carbocyclylthioalkylthiocarbocyclyl, carbocyclylthioalkoxycarbocyclyl, carbocyclyloxyalkylthiocarbocyclyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylthio, heterocyclylamino, heterocyclylalkylamino, heterocyclylcarbonylamino, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy, heterocyclylalkoxycarbonyl, heterocyclyloxyalkoxyheterocyclyl, heterocyclylthioalkylthioheterocyclyl, heterocyclylthioalkoxyheterocyclyl, and heterocyclyloxyalkylthioheterocyclyl. More typically, an aryl or heteroaryl may, for example, optionally be substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SH, xe2x80x94C(O)xe2x80x94OH, amino, aminocarbonyl, amino-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkylthio, carboxy-C1-C6-alkylthio, C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyloxy, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkylthio, C1-C6-alkoxycarbonyl-C1-C6-alkylthio, carboxy-C1-C6-alkoxy, C1-C6-alkoxycarbonyl-C1-C6-alkoxy, aryl, aryl-C1-C6-alkyl, aryloxy, arylthio, aryl-C1-C6-alkylthio, arylamino, aryl-C1-C6-alkylamino, arylcarbonylamino, arylcarbonyl, aryl-C1-C6-alkylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, aryl-C1-C6-alkoxycarbonyl, aryloxy-C1-C6-alkoxyaryl, arylthio-C1-C6-alkylthioaryl, arylthio-C1-C6-alkoxyaryl, aryloxy-C1-C6-alkylthioaryl, cycloalkyl, cycloalkyl-C1-C6-alkyl, cycloalkyloxy, cycloalkylthio, cycloalkyl-C1-C6-alkylthio, cycloalkylamino, cycloalkyl-C1-C6-alkylamino, cycloalkylcarbonylamino, cycloalkylcarbonyl, cycloalkyl-C1-C6-alkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyloxycarbonyl, cycloalkyl-C1-C6-alkoxycarbonyl, heteroaryl, heteroaryl-C1-C6-alkyl, heteroaryloxy, heteroarylthio, heteroaryl-C1-C6-alkylthio, heteroarylamino, heteroaryl-C1-C6-alkylamino, heteroarylcarbonylamino, heteroarylcarbonyl, heteroaryl-C1-C6-alkylcarbonyl, heteroaryloxycarbonyl, heteroarylcarbonyloxy, and heteroaryl-C1-C6-alkoxycarbonyl. Here, one or more hydrogens bound to a carbon in any such group may, for example, optionally be replaced with halogen. In addition, the cycloalkyl, aryl, and heteroaryl are typically single-ring groups containing 3 to 6 ring atoms, and more typically 5 or 6 ring atoms.
In some embodiments, an aryl or heteroaryl optionally is substituted with one or more substituents independently selected from the group consisting of cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocylyloxy, heterocylylthio, heterocylylamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocylyl, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, aminocarbonyl, and aminoalkyl. Here, the amino nitrogen optionally is substituted with:
(i) up two substituents that are independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl, and alkanoyl; or
(ii) two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that:
(a) contains from zero to two additional heteroatoms that are independently selected from the group consisting of nitrogen, oxygen, and sulfur;
(b) optionally is substituted with up to two substituents independently selected from the group consisting of aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocylylalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocylylalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocylylalkoxy, benzofused cycloalkylcarbonyl, heterocyclylalkylcarbonyl, and cycloalkylcarbonyl.
The aminocarbonyl nitrogen is:
(i) unsubstituted;
(ii) the reacted amine of an amino acid;
(iii) substituted with one or two substituents independently selected from the group consisting of alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocylylalkyl, benzofused heterocylylalkyl, benzofused cycloalkyl, and N,N-dialkylsubstituted alkylaminoalkyl; or
(iv) substituted with two substituents such that the two substituents, together with the aminocarbonyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that optionally is substituted with up to two substituents independently selected from the group consisting of alkyl, alkoxycarbonyl, nitro, heterocylylalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl, and amino, wherein the amino nitrogen optionally is substituted with:
(a) two substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl; or
(b) two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring.
The aminoalkyl nitrogen optionally is substituted with:
(i) up to two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl; or
(ii) two substituents such that the two substituents, together with the aminoalkyl nitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring.
A prefix attached to a multi-component group only applies to the first component. To illustrate, the term xe2x80x9calkylcycloalkylxe2x80x9d contains two components: alkyl and cycloalkyl. Thus, the C1-C6-prefix on C1-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C1-C6-prefix does not describe the cycloalkyl component. To illustrate further, the prefix xe2x80x9chaloxe2x80x9d on haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl group is substituted with one or more halogen radicals. If halogen substitution may alternatively or additionally occur on the alkyl component, the group would instead be described as xe2x80x9chalogen-substituted alkoxyalkylxe2x80x9d rather than xe2x80x9chaloalkoxyalkyl.xe2x80x9d And finally, if the halogen substitution may only occur on the alkyl component, the group would instead be described as xe2x80x9calkoxyhaloalkyl.xe2x80x9d
If substituents are described as being xe2x80x9cindependently selectedxe2x80x9d from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).
When words are used to describe a substituent, the rightmost-described component of the substituent is the component that is bound at the location of the replaced hydrogen. To illustrate, benzene substituted with methoxyethyl has the following structure: 
As can be seen, the ethyl is bound to the benzene, and the methoxy is the component of the substituent that is the component furthest from the benzene. As further illustration, benzene substituted with cyclohexanylthiobutoxy has the following structure: 
When words are used to describe a linking element between two other elements of a depicted chemical structure, the rightmost-described component of the substituent is the component that is bound to the left element in the depicted structure. To illustrate, if the chemical structure is Xxe2x80x94Lxe2x80x94Y and L is described as methylcyclohexanylethyl, the chemical would be X-ethyl-cyclohexanyl-methyl-Y.
When a chemical formula is used to describe a substituent, the dash on the left side of the formula indicates the portion of the substituent that is bound at the location of the replaced hydrogen. To illustrate, benzene substituted with xe2x80x94C(O)xe2x80x94OH has the following structure: 
When a chemical formula is used to describe a linking element between two other elements of a depicted chemical structure, the leftmost dash of the substituent indicates the portion of the substituent that is bound to the left element in the depicted structure. The rightmost dash, on the other hand, indicates the portion of the substituent that is bound to the right element in the depicted structure. To illustrate, if the depicted chemical structure is Xxe2x80x94Lxe2x80x94Y and L is described as xe2x80x94C(O)xe2x80x94N(H)xe2x80x94, the chemical would be: 
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d is used adjectivally in this patent to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.
With reference to the use of the words xe2x80x9ccomprisexe2x80x9d or xe2x80x9ccomprisesxe2x80x9d or xe2x80x9ccomprisingxe2x80x9d in this patent (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent, including the claims below.